PROJECT SUMMARY/ABSTRACT Heterocycles are ubiquitous in small molecule drugs and natural products. Modifying such heterocycles to include quaternary centers may impart a number of beneficial effects on pharmacological properties, including increasing binding affinity, increasing solubility or membrane permeability, increasing metabolic stability, and reducing hERG binding. Using our recently developed enantioselective decarboxylative allylic alkylation method, we can now synthesize ?-quaternary centers in a highly enantioselective manner. This project?s overall goal is to provide proof of principle that quaternary heterocycles impart advantages to drug-like molecules. Specifically, our three specific aims serve as case studies to demonstrate the potential advantages of incorporating quaternary centers into heterocycle-containing drugs. In aim I, we will synthesize and evaluate tetra-substituted morpholino derivatives of the antibiotic linezolid to test the hypothesis that tetra-substitution will reduce metabolic clearance, thus reducing the dosage frequency of the drug. In aim II, we will expand our enantioselective allylic alkylation method to synthesize ?-quaternary ?-lactams. We will then apply the method to synthesize and evaluate analogs of the antibiotic meropenem to test the hypothesis that ?-quaternary meropenem analogs will have increased spectrum of activity, including activity against meropenem-resistant bacterial strains. In aim III, we will synthesize and evaluate quaternary piperidine derivatives of the cancer drug ceretinib to test two hypotheses: first, that quaternary centers can access novel binding sites on target enzymes to circumvent resistance in cancer cell lines harboring the clinically significant resistance mutation G1202R; second, that quaternary centers can reduce hERG binding, leading to reduced incidence of QT prolongation. Anticipated outcomes from successful completion of these specific aims, aside from the design of new lead antibiotic and anti-cancer small molecules, include two broadly impactful results: first, this method will provide a new chemical platform to improve the drug-like properties of drugs that contain heterocycles, imparting significant benefits to patients. Second, demonstration of the beneficial pharmacological effects of quaternary heterocycles will warrant their inclusion as privileged motifs in the design of chemical libraries, further expanding the diversity of existing small molecule libraries. Such diversified chemical libraries will facilitate the discovery of quaternary-enhanced hits during high-throughput biological screening against various targets.